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Koonlawee Nademanee, M.D, FHRS, FACC, FAHA, CCDS.Distinguished Professor of Medicine

Chulalongkorn University, Thailand & Bumrungrad Hospital, ThailandPacific Rim Research Institute in Los Angeles & Bangkok, Thailand

Disclosure Statement

• Honorarium & Consultation

Medtronic Inc.

Biosense Webster Inc.

• Research Fundings.

Medtronic Inc.

Biosense Webster Inc.

• Royalty

Biosense Webster Inc

Funding Sources• Thai National Research Council .

• CAPRE (Cardiac Arrest Prevention Research and Education) Foundation of Thailand.

• Grant-in Aid from Adventist Health Care at White Memorial Medical Center, Los Angeles.

• Biosense-Cordis Webster, Inc.

• Grant-in-Aid Bumrungrad Hospital

• Grant-in-Aid Bangkok Medical center & Vejdusit Foundation Bangkok Thailand.

• Grant-in-Aid Medtronic, Inc

SGUL-London

• Elijah Behr• Magdi Saba

Netherlands

• Arthur Wilde• Pieter • Japp Jan Smit

Thailand

• Gumpanart Veerakul• Apichai Khongphatthanayothin• Montawatt Amnueypol• Tachapong Ngarmukos

Japan

• Akihigo Nogami• Hiroshi Nakagawa

Others

• USA• Vietnam (Tuan

Nguyen Xuan)• Burma• Cambodia

Bordeux

• Michel Haïssaguerre• Meleze Hocini• Frederic Sacher

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Discussion Outlines

• Underlying Electrophysiologic mechanisms-Evidence of depolarization abnormality

• Brugada Syndrome substrates-Characteristics and Pathology of the

Substrates.-Ablation of the substrates.

• Combined BrS and ER syndrome

• A World-Wide Brugada Ablation of VF Substrate OngoingMulticenter (BRAVO) Registry

Brugada Syndrome: Underlying Electrophysiologic Mechanisms

• Repolarization disorder.

• Depolarization Disorder,

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Intrinsic

HeterogeneityAccentuate Notch &Cause Loss of APDDome in

EpicardiumDispersion of Repolarization

Transmural Epicardial

QT interval Phase 2 reentry

ST Segment(Vulnerable Window)

Extrasystole

VT/VF

(Reentry)

Brugada Syndrome

INa, ICaIto, IKr, IKs, IK-ATP,

ICl(Ca)

Transmural Dispersion of

RepolarizationPhase 2 Reentry

in RV Epicardium

Phase 2 Reentry-induced VT/VF

Epi 1

Epi 2

ECG

500 msec

50mV

50mV

0.5mV

50mV

200 msec

0

0

0

0

4 3

21

200 msec

50mV

0 0 0

Epi M Endo

4

3

2

1

Section of RVOT myocardium,

showing prominent fatty

infiltration

Area of RVOT myocardium, showing interstitial fibrosis (red) in addition to slight fatty infiltration

Ruben et al. Circulation 2005;112;2769-2777

Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011; 123: 1270-1279.

Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A, Jirasirirojanakorn K, Likittanasombat K, Bhuripanyo K, Ngarmukos T .

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Nademanee et al. Circulation; 2011; 123; 1270-1279Nademanee et al. Circulation; 2011; 123; 1270-1279

Summary

• Abnormal delayed depolarization – Identified exclusively over anterior RVOT

epicardium.– Characterized by abnormal prolonged

fractionated late potentials. • Catheter ablation over this area of abnormal

potentials.– Normalization of the Brugada ECG pattern– Preventing VT/VF episodes, both

spontaneously occurring or induced via PES.

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Summary

• Abnormal delayed depolarization – Identified exclusively over anterior RVOT

epicardium.– Characterized by abnormal prolonged

fractionated late potentials. • Catheter ablation over this area of abnormal

potentials.– Normalization of the Brugada ECG pattern– Preventing VT/VF episodes, both

spontaneously occurring or induced via PES.

Fractionatedelectrogram

de Bakker J M , and Wittkampf F H Circ Arrhythm Electrophysiol. 2010;3:204-213

J Am Coll Cardiol 2015;66:1976–86

Fibrosis, Connexin-43, and ConductionAbnormalities in the Brugada Syndrome

Koonlawee Nademanee, MD,* Hariharan Raju, PHD, Sofia V. De Noronha, PHD, Michael Papadakis, MD,Lanurence Robinson, MBBS, Stephen Rothery, BSc, Naomasa Makita, MD, Shinya Kowase, MD,Nakorn Boonmee, MD, Vorapot Vitayakritsirikul, MD, Samrerng Ratanarapee, MD, Sanjay Sharma, MD,Allard C. Van der Wal, MD, ** Michael Christiansen, MD, Hanno L. Tan, MD, ** Arthur A. Wilde, MD, **

Akihiko Nogami, MD, Marry N. Sheppard,MD, Gumpanart Veeakul, MD, Elijah R. Behr, MD

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Reduced Cx43 Expression

Control BrSvs

Open Heart Epicardial Ablation

** Biopsy site

* *

Epicardial Fibrosis

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Interstitial, Epicardial and Focal Replacement FibrosisECG Changes

Pre-Ablation Post-Ablation Post-Ablation-Ajmaline

** Epicardial Biopsy

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Overlapping Cardiomyopathy & Arrhythmia Phenotype

• Is BrS a subclinical cardiomyopathic disease or ionchannelopathy or both?

• A generalized disease of:

-Myocardial architecture

-Myocyte electrical coupling

-Predilection for severity in RVOT

Mechanism of conduction abnormalities ?

Conduction hypothesis

• Zigzag conduction (increased distance)

• Reduced electrical coupling

• Reduced excitability

• Current-to-load mismatch

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CB CB CB

320 ms 390 ms 230 ms

120 ms 150 ms

CB

Normal

excitability

Re-entry after

INa reduction

Arrhythmias in conduction hypothesis

Subepicardium

A 52 year old Thai male who had out of hospital cardiac arrests. ICD was implanted with sporadic ICD discharged for occasional VF episodes. 10 Years after index events, he experienced an ICD storm due to recurrent VF episodes

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CardioInsight WorkflowWORKFLOW STEPS AND PRACTICAL CONSIDERATIONS

Place the sensor vest on patient

CT Scan to define heart-torso geometry

Record VF data in EP lab

• Induce VF & record using CIT system

37z

Introduction: CardioInsight | Confidential

15 min

Create and display 3D electro-anatomical maps

Manual heart and vest segmentation

▪CIT personnel will place vest and operate system▪Entire workflow (including CT) must be done on same day ▪CT scan (attached)

▪Field of view (FOV) includes the entire patient torso▪Requires saving DICOM images to CD or USB stick

▪Navigation patches underneath vest could decrease mapping resolution

15 min 30 min 5-30 min 2 min per single beat map

2

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2

Propagation movie

Figure-of-eight at RVOT Septal focal

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Conclusions

• In vivo evidence in BrS

•Normal imaging BUT:

Epicardial conduction delay

Correlation with, interstitial and focal fibrosis

Ablation abolishes type 1 pattern and VF

Strongest data yet to support

depolarization hypothesis

Baseline Ajmaline

BrS Substrates are Expansive

• Abnormal low-voltage late potential fractionated signals:

– Not exclusively over anterior RVOT epicardium but also commonly present in the RV body and inferolateral aspect of the RV epicardium

How & WhenTo

Ablate Brugada Substrate

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When to Ablate BrS Substrates:HRS/EHRA/APHRS Expert Consensus Statement on the Diagnosis and

Management of Patients with Inherited Primary Arrhythmia Syndrome

Class IIb

• Quinidine may be considered in asymptomatic patients with a diagnosis of BrS with a spontaneous type 1 ECG.

• Catheter ablation may be considered in patients with a diagnosis ofBrS and history of arrhythmic storms or repeated appropriate ICD shocks.

How to Ablate BrS Substrates

1. Detail Epicardial and Endocardial mapping.

2. Use of Sodium Channel blockade to enhance the BrS substrates.

- Ajmaline, Procainamide, Flecainide, pilsicainide.

- Warm saline

New Ablation End Points

Primary End Point:

❖Elimination of all abnormal late-fractionated electrograms.

Secondary End Point:

❖ Non – inducible VT/VF.

❖ Normalization of the BrS ECG pattern.

How to Ablate BrS Substrates

1. Detail Epicardial and Endocardial mapping.

2. Use of Sodium Channel blockade to enhance the BrS substrates.

- Ajmaline, Procainamide, Flecainide, pilsicainide.

- Warm saline

3 Use of saline-irrigated tip catheter, preferably withcontact sensor

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VDOไฟล์ไมข่ึน้

BrS Treatment Options

• ICD.

• Quinidine.

• Ablation

Brugada J, Papone C Cir Arrhyth Electrophysiology 2015 Increase in Ablation Treatment For BrS

Study N Age/ Male (%) Spont-BrS ECG

History of VT/VFepisodes (%)

SCN5A(%)

ICD(%)

Nademanee 60 34 (100%) (75%) 100% 10% 100%

Papone et al 135 39 (78%) (23%) 47% 24% 100%

Zhang et al 11 48 (100%) 82% 100% 40% 73%

Chung et al 15 41 (100%) 53% 100% 20%

CombinedSeveral Case reports

12 30-40 100% 100% NA 100%

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BrS ERS YS

A 33 years old male with a history of aborted sudden cardiac death with multiple ICD discharges: (BH 7)

Co-Localizing of VF Drivers and abnormal Fractionated EGM

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Co-Localizing of VF Drivers and abnormal Fractionated EGM

Distribution of VF Substrates

100%

21%21%

2%

A World-Wide Brugada Ablation of VF Substrate Ongoing Multicenter (BRAVO) Registry

• 106 BrS with ICD (median age =38; 1 Female)

- 90 cardiac arrest survivors

- 16 Syncope

• 98 Percutaneous epicardial ablations.

• 8 Open thoracotomy ablation

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106

Symptomatic BrS

79

Brugada ECG pattern only

73

Normalized EKG

All had no VF recurrence

(100%)

6 Brugada ECG presence

3 VF recurrence

(50%)

27

Brugada + ER

Pattern

19

BrS EKG normalized

3 VF recurrence

(16%)

8 BrS or ER presence

5 VF recurrence

(63%) * * *

* Repeat ablations

1st Ablation

Outcomes of Ablations: BRAVO(N = 106; follow-up period = 39 ±30 months)

> 10 VF-

shocks

5-9 VF-

shocks

1-4 VF-

shocks

0 VF-

shocks

Pre-ablation 39 22 33 12

(11%)

After 1ST ablation 0 1 18 87

(82%)

After last ablation

(mean 1.2± 0.6)

0 0 4 102

(96%)

Conclusion

Patients with a pure Brugada syndrome without concomitant Early repolarization syndrome who has normal EKG after catheter ablation of the BrS substrates, especially after sodium channel blockade could possibly be treated without ICD.

Curing Brugada Syndrome?Key Questions

• Do we understand the substrates and underlying electrophysiologic mechanisms?

-Substrate change over a period of time?

• Effects of Ablation?

-How does one know that durable and permanent lesions have been achieved?

- No residual substrates left behind?

-Can ablation cause another arrhythmogenic site?

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Ultimate Questions

If the Brugada ECG pattern in BrS patients is completely eliminated by ablations, do they then have no more risk of VF occurrence or sudden cardiac death and do not need ICD?

BRAVE STUDY DESIGN